ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1304G>A (p.Arg435Lys) (rs398122725)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000077658 SCV000488463 uncertain significance Breast-ovarian cancer, familial 2 2016-04-06 criteria provided, single submitter clinical testing
GeneDx RCV000218740 SCV000279207 uncertain significance not provided 2018-07-30 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.1304G>A at the cDNA level, p.Arg435Lys (R435K) at the protein level, and results in the change of an Arginine to a Lysine (AGA>AAA). Using alternate nomenclature, this variant would be defined as BRCA2 1532G>A. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA2 Arg435Lys was not observed in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Arg435Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000704661 SCV000833617 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 435 of the BRCA2 protein (p.Arg435Lys). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 91750). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Sharing Clinical Reports Project (SCRP) RCV000077658 SCV000109461 uncertain significance Breast-ovarian cancer, familial 2 2007-08-02 no assertion criteria provided clinical testing

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